Pyran-core small molecules inhibit basal-like triple-negative breast cancer via proteasome activity

This study investigates the nonsymmetrical pentanoid derivative 5e as a selective anticancer agent against basal-like triple-negative breast cancer (TNBC). The pyran-core derivative 5e demonstrated significant selectivity, effectively suppressing the proliferation of basal-like TNBC HCC-1806 cells (IC₅₀ = 0.59 ± 0.16 µM; selectivity index = 2-6). Mechanistic studies indicated that 5e attenuates proteasome degradation activity via the ubiquitin-proteasome pathway. By promoting the accumulation of ubiquitinated oncoproteins, 5e induces G2/M cell cycle arrest and triggers both early and late apoptosis in HCC-1806 cells. Molecular docking simulations further revealed that 5e forms stable interactions with the β5 subunit binding site of the 20S proteasome.